Inbred SENCARA/Pt mice are susceptible to the induction of benign and malignant skin tumors, developing >0.6 carcinomas/mouse when treated by standard initiation-promotion protocols. Crosses between SENCARA/Pt and resistant BALB/cAnPt mice revealed that resistance is incompletely dominant and that multiple genes determine susceptibility. A genome scan led to the identification of a major locus controlling susceptibility on chromosome 5 in a 21 cM interval between D5Mit259 and D5Mit369. One candidate gene on chromosome 5 is the chemokine MGSA. Transgenic mice with the MGSA gene targeted to skin are 3-fold more susceptible to the induction of skin tumors than control mice. Possible modifier loci are indicated on chromosomes 9, 11 and 12. Congenic mice bred with the susceptibility region of chromosome 5 from SENCARA/Pt mice on a BALB/cAnPt background did not develop more tumors than BALB/cAnPt mice, indicating that this chromosomal region alone is not sufficient to account for susceptibility. A larger series of backcross mice has been bred to determine whether the genes responsible for development of benign and malignant skin tumors are the same or different. Marked synergism for tumor promotion between the phorbol ester 12-O-tetradecanoyphorbol-13-acetate (TPA)and agents that elevate intracellular calcium, such as thapsigargin or the calcium ionophore ionomycin, suggests a role for calcium in tumor promotion by phorbol esters. Synergism was seen only at suboptimal doses of TPA. The mechanism by which elevation of calcium increases promotion by TPA may involve a conventional isoform of protein kinase C (such as protein kinase C alpha) or another calcium-activated pathway. Activating mutations in the K-ras oncogene, which are rarely seen in mouse skin tumors, are frequent in rapidly-arising papillomas and carcinomas on the skin of mice initiated by N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and promoted by mezerein. Only a few K-ras</> mutations were seen in skin tumors from MNNG-initiated mice promoted with TPA. Mouse skin tumors initiated by 7,12-dimethylbenz[a]anthracene and promoted by either TPA or mezerein display mutations in H-ras</> but not Kiras</>. The mechanism of the selective action of mezerein in the promotion of MNNG-initiated skin tumors may be related to the K-ras</> and mezerein- activated protein kinase C pathways in skin. - carcinoma, chemokine, initiation, phorbol ester, promoter, Ras, susceptibility/resistance genes, - Neither Human Subjects nor Human Tissues